The aim of this proposed research is to determine means of controlling drug and ethanol metabolism in perfused rat liver, in vivo, and ultimately in man. First, a clearer understanding of the quantitative contribution of the pathways involved in ethanol metabolism (alcohol dehydrogenase and catalase) in liver will be necessary. Whether or not a third system different from catalase exists in the microsomal fraction requires further evaluation. Control of the rate of metabolism of alcohol (e.g. activation of ethanol metabolism) will be studied in experimental animals and man. Activation of the catalase pathway coupled with inhibition of the NAD+-mediated alcohol dehydrogenase pathway may allow accelerated rates of ethanol metabolism and at the same time obviate the known detrimental side-effects of NADH redox changes. Moreover, attempts to understand the pathways involved in the adaptive increase in ethanol metabolism due to chronic pretreatment with ethanol will be expanded. Investigations of the effect of glucose and lipid synthesis on drug metabolism, and possible metabolic differences in nutritional parameters between normal and alcoholic pretreated animals in relation to their ability to metabolize dangerous drugs will be performed. Finally, an evaluation of the mechanism of physical dependence upon alcohol will be initiated.